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Page 4 of 17 Li et al. J Cancer Metastasis Treat 2020;6:14 I http://dx.doi.org/10.20517/2394-4722.2020.27

Tissue agnostic: patient selection based on common
genetic alteration, not limited by tumor type

Figure 1. Tissue-agnostic approach offers biomarker-informed treatment strategy regardless of histological origin of the tumor

standard therapy. The approval was based on clinical outcome in 54 adult patients across three multicenter,
single-arm, clinical trials: ALKA, STARTRK-1 (NCT02097810), and STARTRK-2 (NCT02568267). The
identification of positive NTRK gene fusion status was determined in local laboratories or a central
laboratory using nucleic acid-based tests prior to enrollment. Among 54 adult patients, the ORR was 57%,
with 7.4% of patients achieving CR. The most common cancers were sarcoma, NSCLC, mammary analog
secretory carcinoma, breast, thyroid, and colorectal. Compared to larotrectinib, the patient populations
[20]
of entrectinib leaned more heavily on adult patients with more prior lines of therapies . Importantly,
entrectinib also showed meaningful responses in brain cancer patients and those whose tumors
[21]
metastasized to the brain .
The approvals of these tissue-agnostic therapies represented a new paradigm in cancer treatment and
validated the notion that, under certain circumstances, the biomarker in essence, rather than the tissue
origin, would define the disease [Figure 1].

It is important to point out that the latest tissue-agnostic approvals are both small molecule receptor
tyrosine kinase (RTK) inhibitors that treat oncogenic fusions in rare tumors. There are a number of novel
[22]
compounds in development for other oncogenic fusion genes , and it is highly likely that next tissue-
agnostic approval will be from one of these experimental agents.

ONCOGENIC GENE FUSIONS
In the past several decades, cancer epidemiological and molecular studies have identified a variety of
genetic alterations including point mutations, chromosomal rearrangements and translocations, gene
[10]
amplification, and overexpression that are believed to play a driver role in various cancer histologies .
Many of these changes lead to constitutive activation of the oncoprotein and downstream signaling
pathways, resulting in uncontrolled cell proliferation, survival, and migration, which are hallmarks of
cancer .
[23]